This is a competitive renewal designed to provide a better understanding of the neurobiological determinants of increased risk for alcohol dependence (AD) and other substance use disorders (SUD) in offspring of AD women. This application is enriched by a longitudinal resource that includes a median 10 year follow up of offspring from high risk (HR) multiplex alcohol dependence families and low risk (LR) families. A total of 1167 day long clinical evaluations, measures of environmental variation, ERP recordings to identify P300 amplitude have been performed that spans childhood, adolescence and young adulthood. The initial two awards recruited and characterized women from multiplex AD families, their siblings and parents. Subsequently, offspring of these women were followed prospectively along with census matched control children with data obtained at yearly intervals covering multiple domains of inquiry. During the last award, we identified factors influencing the presence and age of onset for childhood psychopathology and the onset to begin regular drinking. We propose a multivariate approach for understanding how brain morphology and functioning in HR offspring impacts their tendency for emotional dysregulation, behavioral disinhibition, and greater SUD. Alterations in brain systems involved in cognition, emotion and altered sensitivity to acquired reinforcers (rewards) are prominent in long term alcoholics. The limbic aspects of this circuitry include the orbitofrontal cortex and amygdala. Changes in this circuitry associated with behavioral disinhibition can be informative regarding AD etiology. Familial risk group differences in OFC and amygdala volume and connectivity (diffusion tensor imaging [DTI]) will be studied in HR and LR offspring and related to multiple behavioral measures of disinhibition (Aim 1).
Aim 2 will study prenatal environmental exposures (E) that may produce structural alterations in these key components of brain networks designed for emotional and cognitive regulation and reward. The potential G X E interaction of familial/genetic loading (G) with this exposure will be tested for its effect on these structures.
Aim 3 will determin if trajectories of P300 amplitude, an indicator of behavioral disinhibition, are related to OFC brain morphology and SUD. Using prospectively collected data, Aim 4 will examine the effects of postnatal stressors on brain morphology, and as an exploratory focus, test for potential G X E interactions using specific gene variants. Continued follow-up of these offspring to determine SUD outcome in young adulthood can: (1) provide significant clues about the neurobiological underpinnings of multigenerational AD, (2) suggest G X E interactions influencing neurobiological variation, and (3) allow our prospective childhood/adolescent antecedent data to payoff. Importantly, studying the genetic and environmental determinants of brain morphology involved in SUD has the potential for identifying offspring at highest risk for possible intervention and prevention of SUD.

Public Health Relevance

This is a competitive renewal of a program of research designed to provide a better understanding of the neurobiological determinants and consequences of alcohol dependence (AD) in women from families with multiple cases of AD and their offspring. Currently, there is no way to identify which offspring will survive or succumb to AD or related substance use disorders. This study would provide continued young adult follow up to determine offspring SUD outcome, measure brain regions thought to be involved in SUD in these offspring and controls, relate the brain morphology to familial loading for AD and environmental exposures including prenatal exposure to alcohol, thereby providing important clues concerning the neurobiological underpinnings for multigenerational AD and suggest possible interventions.

Agency
National Institute of Health (NIH)
Institute
National Institute on Alcohol Abuse and Alcoholism (NIAAA)
Type
Research Project (R01)
Project #
5R01AA008082-20
Application #
8270518
Study Section
Neural Basis of Psychopathology, Addictions and Sleep Disorders Study Section (NPAS)
Program Officer
Chiapella, Page
Project Start
1990-01-01
Project End
2015-04-30
Budget Start
2012-05-01
Budget End
2013-04-30
Support Year
20
Fiscal Year
2012
Total Cost
$645,957
Indirect Cost
$209,766
Name
University of Pittsburgh
Department
Psychiatry
Type
Schools of Medicine
DUNS #
004514360
City
Pittsburgh
State
PA
Country
United States
Zip Code
15213
Lichenstein, Sarah D; Jones, Bobby L; O'Brien, Jessica W et al. (2014) Familial risk for alcohol dependence and developmental changes in BMI: the moderating influence of addiction and obesity genes. Pharmacogenomics 15:1311-21
O'Brien, Jessica W; Lichenstein, Sarah D; Hill, Shirley Y (2014) Maladaptive decision making and substance use outcomes in high-risk individuals: preliminary evidence for the role of 5-HTTLPR variation. J Stud Alcohol Drugs 75:643-52
Hill, Shirley Y; Jones, Bobby L; Holmes, Brian et al. (2013) Cholinergic receptor gene (CHRM2) variation and familial loading for alcohol dependence predict childhood developmental trajectories of P300. Psychiatry Res 209:504-11
Hill, Shirley Y; Terwilliger, Robert; McDermott, Michael (2013) White matter microstructure, alcohol exposure, and familial risk for alcohol dependence. Psychiatry Res 212:43-53
Hill, Shirley Y; Tessner, Kevin D; McDermott, Michael D (2011) Psychopathology in offspring from families of alcohol dependent female probands: a prospective study. J Psychiatr Res 45:285-94
Hill, Shirley Y; Wang, Shuhui; Carter, Howard et al. (2011) Cerebellum volume in high-risk offspring from multiplex alcohol dependence families: association with allelic variation in GABRA2 and BDNF. Psychiatry Res 194:304-13
Hill, Shirley Y; Tessner, Kevin; Wang, Shuhui et al. (2010) Temperament at 5 years of age predicts amygdala and orbitofrontal volume in the right hemisphere in adolescence. Psychiatry Res 182:14-21
Tessner, Kevin D; Hill, Shirley Y (2010) Neural circuitry associated with risk for alcohol use disorders. Neuropsychol Rev 20:1-20
Hill, Shirley Y; Wang, Shuhui; Kostelnik, Bryan et al. (2009) Disruption of orbitofrontal cortex laterality in offspring from multiplex alcohol dependence families. Biol Psychiatry 65:129-36
Hill, Shirley Y; Steinhauer, Stuart R; Locke-Wellman, Jeannette et al. (2009) Childhood risk factors for young adult substance dependence outcome in offspring from multiplex alcohol dependence families: a prospective study. Biol Psychiatry 66:750-7

Showing the most recent 10 out of 43 publications