Individuals with FAS are at heightened risk for alcohol use disorders;however, this issue has not been experimentally tested with an animal model similar to humans. Moreover, fetal alcohol-exposed children are often conceived within the context of a stressful environment, yet interactions between prenatal alcohol exposure (PN Alc) and prenatal stress (PN Stress) are an understudied yet common condition in children. We have a unique resource of 40 adult rhesus monkeys identical in rearing history and age- and gender-matched across conditions of PN Alc exposure, PN Stress, and the combination of PN Alc and PN Stress exposure. Our first step in this longitudinal study was to describe the behavioral phenotype associated with these PN conditions. In the second step, we assessed dopaminergic function and glucose metabolism underlying the behavioral phenotype using high resolution PET imaging. The third step, proposed in this application, is to determine whether the prenatal treatments create a "self-medicating phenotype". In other words, our objective is to determine whether monkeys exposed to prenatal perturbations, that we have found to cause altered serotonin and dopamine function, show heightened risk for excessive voluntary alcohol consumption and associated neuroadaptational changes in the brain compared to controls. This will move the field forward, leading to a better understanding of the interrelationships of 5-HT and DA synaptic constituents related to alcohol use disorders and the development of novel therapeutic strategies. Examining groups of anatomical regions which are components of a functional circuit is a valuable path toward identifying a biomarker for a disease. We will employ a state-of-the-art alcohol self-administration paradigm developed by Grant and colleagues (Vivian et al., 2001), which is the gold standard for the field. Our high resolution PET scanner is situated in our animal facility and we have a highly skilled, experienced team of collaborators to ensure rigorous data acquisition and analysis. We will assess neurochemical functioning both at baseline (before drinking) as well as immediately following chronic alcohol self-administration (4%, 22 hr/day for 6 months). We will test whether pre-drinking (baseline) 5-HT1A, D1, and D2 receptor and DA transporter binding predict chronic alcohol consumption levels. Multiple scans with different tracers in the same monkeys will yield a more complete picture of interrelated 5-HT and DA processes before and after chronic alcohol consumption.
Increased knowledge of the neurocircuitry of alcoholism could assist in developing new pharmacological treatments and facilitate shaping interventions to fit subgroups at risk. Moreover, research has shown that early interventions to address the neurodevelopmental needs of children with FASD improve long-term developmental outcomes. Our results would support increased early prevention and interventions that could prevent or reduce alcohol use disorders in FASD children and other children of alcoholics growing up in stressful environments.
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