Marc A. Schuckit - US grants

The proposed work is based on the premise that: first, alcoholism is genetically influenced; second, studying children of alcoholics might help identify potential markers of a predisposition towards alcoholism; and third, on data demonstrating that sons of alcoholics (FHPs) show a decreased intensity of reaction to ethanol when compared to sons of nonalcoholics. Our immediate goals are to further characterize this decreased intensity of reaction to ethanol, to begin to narrow down the number of potential psychological/cognitive contributors to this phenomenon, and to hone in on possible physiological/biochemical mechanisms contributing to the decreased intensity of reaction in FHPs. We propose to begin to accomplish these tasks by using our research approach to determine the generalizability of the decreased reaction to ethanol to the level of reaction to another CNS depressant, diazepam. In this proposal, healthy, drinking and nonalcoholic sons of alcoholics age 21 to 25 will be matched with sons of nonalcoholics on demography, drinking and drug use histories, and height to weight ratio. Selected individuals will then be brought to the laboratory on 4 occasions where they will be challenged in turn with 0.7 ml/kg of ethanol plus palcebo diazepam, 0.1 mg/kg of diazepam plus palcebo ethanol, 0.2 mg/kg of diazepam plus ethanol, and placebo ethanol plus placebo diazepam and their reactions observed over the subsequent four hours. The intensity of reaction tot he challenge drug will be monitored through subjective and observer ratings of levels of intoxication, cognitive/psychomotor measures before and after the drug challenge, and hormonal responses during the laboratory session.

DESCRIPTION (provided by applicant): This is a revised application with the goal of evaluating how a low level of response (LR) to alcohol relates to other domains in a person's life (e.g., drinking among peers, ways of coping with stress, etc.) to increase the risks for heavy drinking and alcohol-related problems in teenagers and young adults. The evaluations focus on an LR-Social Information Processing Model which is studied in the second generation from 437 families that represent a 97% follow-up of eligible pedigrees over a 20-year period. We propose to test the model during the 25-year follow-up when the offspring, the major focus of this work, will be relatively young. Data will be gathered directly from sons and daughters age 12 and above, as well as from the parents. The major analyses will test the full model on an estimated 250 drinkers from among the 327 offspring age 12-24. At the core of the model are the family history of alcoholism and the low LR to alcohol. We hypothesize that a low LR might alter a person's expectations of the effects of alcohol which then enhances the probability of using alcohol to cope with stress. The initial need for higher amounts of alcohol for effects might also enhance the probability of acquiring heavy-drinking friends, who then increase the likelihood of alcohol problems. The family history of alcoholism is projected to be associated with a child's observing heavy drinking in the home, which also affects the selection of heavy-drinking friends and problematical coping mechanisms. The revised application expands the background information on the self-report measure of the level of response to alcohol, presents specific power calculations relevant to the structural equation modeling approach being used, and demonstrates how age, gender, ethnic background, and the non-independence of ratings among siblings can be modeled within the analyses to enhance understanding of how a low LR operates in teenagers and young adults. Our ultimate goal is to identify ways to prevent the escalation of drinking and associated problems in young populations.

[unreadable] DESCRIPTION (provided by applicant): The primary aim of the revised application is to understand cognitive features and brain systems that differentiate low- and high-level responders to alcohol, while under the influence of alcohol and without alcohol intoxication. Participants will be young adults ages 18-25 with the following exclusions: history of substance dependence or major psychiatric disorder, medical illness or use of medications that might interfere with alcohol challenge or affect brain imaging results, pregnancy, have had unpleasant reactions to moderate alcohol doses, left handed, or magnetic resonance imaging contraindications (e.g., metal, claustrophobia). Participants will be selected from annual mailings to college students, and classified as low or high level responders to alcohol, initially based on a standardized self-report instrument. Potential participants will receive a detailed diagnostic interview, and a traditional alcohol challenge to confirm level of response to alcohol and comfort in consuming moderate doses. Low (n=50) and high (n=50) level responders will be matched on: height, weight, race, gender, and recent use of alcohol, nicotine, and other drugs. Eligible participants will receive functional magnetic resonance imaging (fMRI) two times: after drinking moderate doses of alcohol (up to 0.68 ml/kg alcohol for women and up to 0.75 ml/kg alcohol for men) and after drinking placebo. Order of beverage administration will be randomized. Each fMRI assessment will administer Visual Working Memory and Sensorimotor tasks during blood oxygen level dependent scan acquisition, structural MRI (for spatial localization), and arterial spin labeling (to control blood flow differences). The imaging session will start 30 minutes after beverage administration and last one hour, recording results at rising and falling BACs. The two imaging sessions will occur within the same week. Data will be compared in 2x2 analyses of variance to compare brain activation between low and high level responders with and without alcohol intoxication. These results will potentially develop a method for identifying low responders (a group at high risk for alcoholism) even before their first drink. The project will also expand our understanding of the neural substrates of the level of response to alcohol, a key risk factor for the development of alcohol dependence. [unreadable] [unreadable] [unreadable]

1. An Overview of Subject Selection and Characteristics The original COGA Guidelines for selection of probands, Identiflcation of appropriate relatives, and selection of controls and their families are outiined above. The proposed work will recruit no new families and will only draw upon members of the existing pedigrees. Appropriate members of COGA probands and comparison families will be invited to continue to participate In the prospective panel study, along with children who age up to the 12-year minimum age required for participation. Alcoholic probands had been originally ascertained from consecutive admissions to public and private inpatient and outpatient treatment facilities at each ofthe COGA participating sites. This Included individuals who fulfilled the COGA criteria for alcohol dependence, and who had multiple alcohol-dependent relatives living within 50 to 150 miles ofthe COGA Centers. Comparison families were selected using different methods across the subject collection sites, with approaches including random mailings to individuals affiliated with the respective university, people who are attending dental and medical clinic patients, and a random assessment through public records. Potential probands were excluded from the study if they had a mortal illness, were current IV drug users, reported an extensive history of IV drug use (31+ times), or were known to be infected with the HIV virus. These exclusion criteria are not applied to family members. In general, for all subjects medical or psychiatric conditions were the only general grounds for exclusion if it seemed probable that they might compromise a subject's ability to provide informed consent (e.g., advanced Alzheimer's disease) or hinder one's participation in the blood sampling or electrophysiological portions ofthe study (e.g., liver disease, neurological disease, head injuries, etc.). For the current ongoing study of adolescents and young adults, individuals younger than the age of majority (18 years) are assessed (including direct interviews, neurophysiological and electrophysiological testing, and blood samples) only following written consent is obtained from the parents and assent of the subject. The study of adolescents and young adults is essential to facilitate genetic analyses of characteristics related to the onset of alcohol and substance use and associated problems. These findings will facilitate our understanding of the potential importance of specific genetic markers and enhance our understanding of eariy drinking parameters.

DESCRIPTION (provided by applicant): This revised application evaluates a new approach to decrease heavy drinking and alcohol problems among drinking university students by addressing an individual's specific vulnerability toward these difficulties. We build upon a successful pilot protocol that focused on a relatively prevalent preexisting risk factor for heavy drinking, the low level of response (LR) to alcohol, to diminish the vulnerability toward heavy drinking related to this genetically-influenced need for a higher number of drinks to feel effects. By incorporating existing methods to create a novel and potentially more effective approach, we optimize our ability to compare results to existing state-of-the-art (SOTA) programs, and can use elements of interventions with which university administrators are already familiar and can be instituted at little cost. The proposal is the next logical step from the small pilot project described in A.6213 to determine if the prior positive outcomes remain with a larger population and a 1-yr follow-up, thus setting the potential basis for a more definitive study in the future. questionnaire will be distributed to >4,000 freshmen at UCSD to gather their demography, alcohol histories, and LR. The latter is measured by the retrospective SRE questionnaire where LR is the number of drinks required for a range of effects. Subjects matched on drinking histories will be randomly assigned to: 1) a Low Response-Based Intervention Group (LRB, N=200) where they receive five 45-min. Internet-based videotapes that incorporate the SOTA drinking intervention techniques, but with information structured around the model demonstrating how a low LR to alcohol contributes to later heavy drinking and alcohol problems; 2) a SOTA Group (N=200) where they receive similar state-of-the-art information, but are not taught about LR; or 3) a comparison Assessment Only (AO) Group (N=100) where they receive neither LRB nor SOTA-based information, but will be evaluated on the same time frame as the 2 intervention groups. All subjects will be followed for 12 months. As supported by the pilot data in A.6, Hypothesis 1 is that individuals with lower LRs to alcohol will demonstrate the greatest decreases in heavy drinking and subsequent problems when participating in the LRB Group that focuses on their specific vulnerability. Hypothesis 2 is that those with high LR (while also decreasing heavy drinking in the LRB Group) will show the greatest decreases in a SOTA Group that addresses their vulnerability that is not related to LR, but to impulsivity, mood dysregulation, and other risk factors.11 Hypothesis 3 is that the interventions incorporated in LRB and SOTA protocols will be associated with less future heavy drinking and alcohol problems than are seen in the AO Group. If the hypotheses prove correct, the results may serve as an example of how universities might improve drinking outcomes by tailoring prevention efforts to additional specific preexisting risk factors.

DESCRIPTION (provided by applicant): This revised application builds upon promising pilot data and several recent papers4-9 to request support to more thoroughly evaluate if functional magnetic resonance imaging (fMRI) data add significantly to alcohol challenge-based measures of a low level of response (LR) to alcohol in predicting heavy drinking, alcohol problems and alcohol use disorders. The subjects will be 120 healthy men and women who as non-alcoholic drinkers completed their fMRI evaluations at about age 19, and who would be followed up at about age 25. A low LR (or low sensitivity) to alcohol is a genetically influenced characteristics that can be observed early in life and that predicts later heavy drinking and alcohol-related problems.1-3 Several physiologic correlates of LR have been documented, and the >40% heritability of this low response has been well established. However, each gene explains only a small proportion of the LR risk, and the less intense alcohol-related changes in motor performance, blood hormone levels, and electrophysiologic measures associated with the low LR are so broad in scope that they raise the possibility that the underlying mechanisms of the low LR may involve some overarching cognitive CNS processes, not just the response to alcohol. This conclusion is supported by several prior small-scale fMRI studies of 15-to-25-yr-old healthy, drinking, but non-alcoholic subjects that reported differences between individuals with low and high LRs in neural activity during a cognitive task, even with placebo or with no beverage challenge.4-6 Reflecting these data, in this R21 proposal we hypothesize that the low LR might reflect a relatively general physiological brain characteristic that is present even in th absence of alcohol and that makes it more difficult for a person to recognize the effects of modest alcohol doses. Thus, the fMRI pattern associated with the low LR established in our recent papers may be closer to the general mechanisms that underlie the low LR than the currently available measures of LR itself. Therefore, consistent with our pilot data, the fMRI results may add significantly to the direct measures of LR in predicting adverse alcohol outcomes. To further test this hypothesis, we need to follow up and evaluate the outcomes for the 19-yr-old subjects studied ~5 yrs ago in our prior protocol. If our hypotheses are correct, our findings could lead to the search for more simple and less expensive cognitive or physiological measures of the brain processes related to the low LR. Future studies could also evaluate if measures of the processes that underlie LR can identify the related risk for heavy drinking even before the first drink, which, in turn, might facilitate the early life use of prevention efforts t decrease the risk for alcohol problems.47

The Collaborative Study on the Genetics of Alcoholism (COGA) is a tightly integrated, and interdisciplinary project that involves participation of investigators from multiple sites spanning a broad range of expertise. The goals of COGA are to identify and characterize genes in which variations confer risk for, or protection from, the development of Alcohol Use Disorders (AUDs) and related phenotypes; to understand the mechanisms by which these variants work at the molecular and cellular level; and to understand how genetic, environmental, and neurocognitive factors interact to influence the developmental trajectories of alcohol use and AUDs through an ongoing prospective study of at-risk individuals. COGA has assembled a unique sample of large, ethnically diverse families densely affected by AUDs and a set of comparison families, with rich phenotypic assessments in multiple domains: clinical, behavioral, neurophysiological, neuropsychological and environmental. The overall specific aims are to: Aim 1. Advance understanding of complex phenotypes related to AUDs; Aim 2. Identify additional genes contributing to risk for AUD, related phenotypes, including endophenotypes; Aim 3. Explore potential mechanisms of action of key genes; Aim 4. Examine effects of genes and environmental influences on clinical and neurophysiological phenotypes related to the vulnerability for risky drinking, AUDs and SUDs across development. In responding to the RFA, the study has three inter-dependent projects and three essential cores. The three projects are each focused on different aspects of these core aims: Genetic and Functional Studies of Alcohol Use Disorders and Related Phenotypes - Using a range of alcohol-related phenotypes, identifies variants across allelic spectrum and studies their mechanisms of action; Prospective Study of Genetic and Environmental Influences on Alcohol Use and Disorders Across Development - Longitudinally studies genetic and environmental influences and their interaction on development of AUDs during adolescence and emerging adulthood; Neurophysiological Phenotypes, Brain Maturation and Development of Alcohol Use and Related Disorders - Identifies genes related to novel neurocognitive phenotypes and their effects on trajectories of neurocognitive development and AUDs. The cores (Administrative Core, Data Management Core, and NIAAA/COGA Sharing Repository Core (NCSR)) provide critical support to each project, ensuring that key cross-study and cross site functions are centralized. Through tight coordination of this interdisciplinary study, we will go from identifying genes, in which variants affect risk for AUDs and related phenotypes to understanding how they act at multiple levels, from molecular and cellular, to behavioral, neurophysiological, cognitive phenotypic, as a function of development. The delineation of the pathways and genes contributing to alcohol use and AUDs will impact treatment and prevention of AUDs in those at greatest risk.