The long range objective of this project is to evaluate the role of central nervous system (CNS) serotonin function as a potential mediator of the clustering of health-damaging psychosocial and biobehavioral characteristics in the same individuals and low socioeconomic status (SES) groups.
Specific Aims to achieve this goal are: 1. Use CSF 5-HIAA and behavioral and biological responses to serotonin enhancement and depletion to evaluate CNS serotonergic function in a community sample of normal young adults who are sampled to provide equal numbers with high vs. low SES level, male and female gender, and Black and White race. 2. Determine whether there is an association between lower CNS serotonergic function -- indexed by CSF 5HIAA -- and increased prevalence of the set of psychosocial and biobehavioral risk factors across individuals. 3. Determine whether the expected association between lower SES and increased prevalence of psychosocial and biobehavioral risk factors is weakened or abolished by adjustment for CNS serotonergic function. 4. Determine the effects of acute serotonin enhancement and depletion on biological and mood responses to the lab stressors used in Project 1 among subjects low in SES and CNS serotonin function. We shall recruit a community sample of 400 subjects, stratified as in Aim 1, who will be studied during a 2.5 day admission to our linical Research Center. During that time they will undergo a lumbar puncture to provide cerebrospinal fluid (CSF) for assay of CSF 5-hydroxyindole acetic acid (5HIAA) a reliable measure of CNS serotonin turnover. They will also be subjected to serotonin-depletion using the tryptophan-depletion method and serotonin enhancement using the drug fenfluramine. We shall evaluate and compare the relationship of SES and CSF 5HIAA to the profile of psychosocial and biobehavioral risk factors, and the effects of serotonin depletion and enhancement on measures of mood, cardiovascular and neurodocrine function, as well as on responses of these functions to mental challenge. If we find that CSF 5HIAA relates more strongly to adverse psychosocial and biobehavioral profiles than SES, it will support our hypothesis that CNS serotonergic function is a mediator of the adverse profile per se, as well as of the impact of low SES on the profile. This hypothesis will be further supported if serotonin depletion and enhancement cause an increase and decrease, respectively, in mood and biological indicators of the adverse profile, with differential effects in subjects with high vs. low CSF 5HIAA. Successful achievement of the long range goal of this project would lead to a major increase in our understanding of the neuro- biological basis of the observed clustering of psychosocial, behavioral, and biological risk indicators in certain individuals and low SES groups. Such understanding has the real potential to identify effective preventive and treatment approaches to reduce the toll of cardiovascular disease in the U.S. each year.
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