Scott F. Stoltenberg, Ph.D. - US grants

A primary rationale for the development of alcoholism typologies, and for the identification of alcoholism vulnerability alleles, is to reduce heterogeneity and to provide individualized and effective treatment. Because the serotonin and dopamine neurotransmitter systems have been implicated in the etiology of alcoholism, as well as being systems modifiable by pharmacological agents, they are logical systems on which to focus with respect to treatment outcome. This collaborative project, to be conducted jointly by the applicant and a clinical psychologist, has the following specific aims: (1) to assess whether particular genotypes have an effect on treatment outcome; (2) to assess whether the effect of genotype on treatment outcome is mediated by temperament, specifically in areas having to do with impulsivity, apprehensiveness and social sensitivity; (3) to evaluate possible differences in treatment outcome for individuals assigned to empirically generated subtypes; (4) to evaluate potential associations between alcoholism typology and genotype. A minimum of 300 participants (62 percent men) will be recruited as consecutive admissions to an outpatient treatment center. On intake, participants will self-administer a questionnaire battery assessing alcohol use and the HA, NS and RD temperament dimensions, and will donate 7ml of blood for genetic analysis. Following the intake assessment, a six month follow-up interview will assess alcohol and drug consumption patterns to evaluate treatment efficacy. We will assay genetic markers that are candidates for associations with either temperament and/or with alcoholism: serotonin transporter (5HTTLPR), serotonin 2c receptor (HTR2C), monoamine oxidase A (MAOA) and dopamine receptor D4 (DRD4). Results of this research will be a first step in increasing our understanding of the associations among neurotransmitter systems, alcoholism typology and treatment outcome.

This is an application for a Mentored Research Scientist Development Award (K01). This award is requested to provide an opportunity for the candidate to complete a transition from basic behavior-genetic research to a clinically based program of research focused on understanding the influence of heredity on risk for antisocial alcoholism (AAL) and its comorbid disorders (CDs). The training setting is the University of Michigan Department of Psychiatry and Mental Health Research Institute. It is clear that alcoholism is not a Mendelian trait, the factors associated with its intergenerational transmission are multiple and interacting. This proposal is designed to provide the candidate with experience on several fronts, all of which will be necessary to better understand the complexities of the etiology and developmental trajectories of AAL and its CDs within a developmental systems framework. These fronts include (a) multivariate statistics, (b) molecular genetics, (c) longitudinal/developmental study designs and (d) complex adaptive systems. Implementation of these skills in the conduct of small scale research projects will position the candidate for submission of an R01 application during the award period. This application describes studies that would take place during the MRSDA period that would enable the candidate to enhance his scientific skills along each of these fronts. The major study proposed would serve to collect and archive genetic samples from 291 families participating in the University of Michigan/Michigan State University Longitudinal Study directed by Dr. Robert A. Zucker, that are well characterized phenotypically. Candidate gene analyses will be conducted to assess potential associations between genes in the serotonergic system and behavioral undercontrol in children, a risk factor for developing AAL. This sample represents an important resource to study risk for AAL and its CDs. Archiving the genetic samples will position the candidate to take advantage of expected technological advances in rapid and large-scale scoring of single nucleotide polymorphisms (SNPs) and in complexity-oriented analytic techniques. Other projects proposed include secondary analysis of a family-based genetic study data set, the development of molecular genetic markers and additional candidate gene analyses. This award would enhance the candidate's potential for developing an independent research program to study the genetics of antisocial alcoholism and its comorbid disorders.

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Making decisions in situations where the probabilities of success are either completely unknown (i.e. uncertainty) or known (i.e. risk) is an important part of a person's everyday life and can have significant health consequences. There are individual differences in decision-making that are likely due to a person's biologically based autonomic nervous system reactivity. Genetic variation in components of neurotransmitter systems (e.g. receptors or transporters) is likely to play an important role in autonomic nervous system activation and regulation. Our long-term goal is to facilitate the development of prevention and treatment methods for mental illness and behavioral disorders based on an understanding of the mechanisms that influence the propensity to engage in health-risk behaviors (HRB) via genetic variation in neurotransmitter systems and their subsequent influence on behavior. It is in that context that we are proposing to examine basic mechanisms involved with decision-making. We will test the following hypotheses: a. Measures of autonomic activation are associated with decision-making and with the personality trait Neuroticism. b. Genetic differences on decision-making are mediated by autonomic activation. c. Gender moderates the associations between neurotransmitter genes and decision-making.