Behavior, serotonin and cardiovascular risk

本项目的主要目标是确定心血管疾病的社会心理、社会环境和生活方式相关风险因素是否与中枢神经系统多巴胺能（5-HT）反应性的个体间变异性相关。感兴趣的行为风险因素包括敌意、抑郁、社会经济地位低、社会孤立（低社会支持）、同期压力、吸烟、不谨慎饮食、缺乏身体活动和过度饮酒。第二个目的是确定中枢多巴胺能反应性的个体差异是否也与血管疾病的临床前指标和累积风险因子暴露（即，内皮介导的鳃动脉扩张、颈动脉内膜-中层厚度和动脉粥样硬化斑块）。第三个目的是确定是否可以预测，在部分人口的变化，在中央多巴胺能功能，在5-HT系统的候选基因的多态性变化。我们建议招募600名男性和女性，年龄30-50岁，没有动脉粥样硬化性心血管疾病的临床病史的社区样本。将对受试者进行神经精神药理学激发，以评价中枢催乳素能反应性（血浆催乳素和ACTH对5-HT再摄取抑制剂西酞普兰的反应），并收集上述心血管疾病行为风险领域的数据。后者将包括一系列诊断和评估访谈以及标准化问卷。将对300例受试者进行血管反应性和颈动脉疾病的超声评价，根据中枢5-HT反应性分布的上三分位数和下三分位数得出（根据受试者的西酞普兰诱导的催乳素反应指数）。此外，将从所有研究受试者中采集用于DNA分析的血液。项目1将提供一个假设的第一个系统性检验，即心血管疾病的行为风险的不同来源聚集在一起，部分是在一个共同的神经生物学机制的影响下，涉及改变中枢神经功能。支持这一假说将进一步我们的行为对心脏病的影响的起源的理解，并提供线索的病因学和致病性的可能共性。

The principle objective of this Project is to establish whether psychosocial, socio-environmental and lifestyle-related risk factors for cardiovascular disease are associated, individually and in aggregate, with interindividual variability in central nervous system serotonergic (5-HT) responsivity. Behavioral risk factors of interest include hostility, depression, low socio-economic status, social isolation (low social support), contemporaneous stress, smoking, imprudent diet, physical inactivity, and excessive consumption of alcohol. A second aim is to determine whether individual differences in central serotonergic responsivity also covary with preclinical indicators of vascular disease and cumulative risk factor exposure (viz., endothelium-mediated dilation of the branchial artery, carotid artery intimal-medial thickness and atherosclerotic plaque). A third aim is to determine whether population variability in central serotonergic function may be predicted, in part, by polymorphic variation in candidate genes of the 5-HT system. We propose to recruit a community sample of 600 men and women, 30-50 years of age and without clinical history of atherosclerotic cardiovascular disease. Subjects will be administered a neuropsychopharmacologic challenge to evaluate central serotonergic responsivity (plasma prolactin and ACTH responses to the 5-HT re-uptake inhibitor, citalopram) and data will be collected in each of the foregoing domains of behavioral risk for cardiovascular disease. The latter will include a batter of diagnostic and assessment interviews, as well as standardized questionnaires. Ultrasound evaluations of vascular reactivity and carotid artery disease will be obtained on 300 subjects, derived from the upper and lower tertiles on the distribution of central 5-HT responsivity (as indexed by subjects' citalopram-induced prolactin responses). In addition, blood for DNA analysis will be obtained from all study participants. Project 1 will provide a first systematic test of the hypothesis that diverse sources of behavior risk for cardiovascular disease aggregate, in part, under the influence of a common neurobiologic mechanism involving altered central serotonergic function. Support for this hypothesis will further our understanding of the origins of behavioral influences on heart disease and provide clues to possible commonalities of etiology and pathogenicity.