EFFECTS OF BRAIN SEROTONIN FUNCTION ON CORONARY HEART DISEASE RISK FACTORS

该项目的长期目标仍然是“阐明生物行为因素在冠心病病因、发病机制和病程中的作用”。“我们的三个广泛的计划目标是：1）评估相互关联的心理社会风险因素与行为和生物因素之间的关联。（包括细胞/分子水平）发病机制的介质; 2）识别增加发病机制的心理社会/生物行为特征的环境前因;和3）在人类和动物模型中评价脑多巴胺能功能降低作为某些个体和低SES组中的心理社会和生物行为介质聚集的介质的可能作用，发病机制研究方法：我们正在招募一个由400名受试者组成的社区样本，根据SES、种族和性别进行分层，他们将在2.5天的GCRC住院期间接受研究。在此期间，他们将接受腰椎穿刺，以提供脑脊液（CSF）用于CSF 5-羟基吲哚乙酸（5 HIAA）测定，这是CNS 5-羟色胺转换的可靠指标。他们还将使用色氨酸消耗法进行血清素消耗，并使用iv色氨酸进行血清素增强。我们将评估和比较SES和CSF 5 HIAA与心理社会和生物行为危险因素的关系，以及5-羟色胺耗竭和增强对情绪、心血管和神经内分泌功能的影响，以及对这些功能对精神挑战的反应。结果如下：我们现在已经通过GCRC协议运行了35个受试者（S），并且，按照目前的受试者增加速度，我们预计到7月30日当前资助期结束时，我们将有60多个完成的受试者，使我们能够实现我们的招募目标。根据GCRC方案收集的数据的初步检查显示，所有变量均在预期范围内，并显示预期变化-例如，增加心血管和神经内分泌唤醒与愤怒回忆挑战。色氨酸耗竭方案按预期发挥作用，血浆色氨酸水平在色氨酸耗竭日降至极低水平。现在运行的样本占总样本的17%，我们还没有开始对主要假设进行数据分析。结合上述适当范围和响应度的检查，对目前可用的数据进行检查，发现了一个相当有趣的偶然发现。在色氨酸耗竭组的前11名受试者中，在第一个安慰剂日摄入含色氨酸的氨基酸饮料之前，CSF 5 HIAA高（表明脑5-羟色胺周转率高）的受试者的静息血浆去甲肾上腺素（NE）高于CSF 5 HIAA低的受试者。在饮用饮料后30分钟，所有Ss显示NE的峰值，该峰值在高5 HIAA Ss中更大，尽管它们的基线水平更高。在第二个测试日，在饮用不含色氨酸的饮料后30分钟，高5 HIAA Ss显示出比安慰剂日更大的NE尖峰，而低5 HIAA Ss显示出更小的峰。虽然这一观察结果的最终意义仍有待确定，但非常有趣的是，色氨酸消耗对高与低5 HIAA Ss中血浆NE对令人不快的饮料的反应具有相反的影响-这表明当我们朝着我们计划的、更系统的数据分析前进时，CSF 5 HIAA测量将产生重要的发现。尽管在我们最初的申请中没有提出，但我们一直在收集最近发现的5-羟色胺转运蛋白启动子多态性的试验数据。5-羟色胺转运蛋白的启动子区域在人类中有两个等位基因，一个长（l）和一个短（s）。与l/s或s/s基因型的人相比，l/l基因型的人制造更多的转运蛋白，并且在神经毒性的测量中得分较低。Higley等人最近的一项研究发现，l/l基因型与从出生到六个月大与母亲分离的恒河猴中较高的CSF 5 HIAA水平相关。然而，在母猴中，转运蛋白启动子基因型与CSF 5 HIAA无关。我们将能够在我们的GCRC方案下正在研究的受试者中评估这种相同的关系-即，以测试I/I基因型是否在较低SES的Ss中比在较高SES的Ss中更强地与较高CSF 5 HIAA相关。重要性：研究结果应加强我们对心理社会/生物行为风险因素聚集的环境和神经生物学基础的理解，并导致心血管疾病预防和治疗的改进方法。

The long term objective of this program project continues to be "to elucidate the role of biobehavioral factors in the etiology, pathogenesis and course of coronary heart disease (CHD)." Our three broad, programmatic objectives are to: 1) Evaluate the association between interrelated sets of psychosocial risk factors and behavioral and biological (including the cellular/molecular level) mediators of pathogenesis; 2) Identify environmental antecedents of the psychosocial/biobehavioral profile that increases pathogenesis; and 3) Evaluate in both humans and an animal model the possible role of reduced brain serotonergic function as a mediator of the clustering in certain individuals and low SES groups of psychosocial and biobehavioral mediators of pathogenesis. Methods: We are recruiting a community sample of 400 subjects, stratified on SES, race, and gender who will be studied during a 2.5 day admission to our GCRC. 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 iv tryptophan. 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. Results: We have now run 35 subjects (Ss) through the GCRC protocol, and, at the present rate of subject accrual, we anticipate that by the end of the current grant period on 30 July we will have over 60 completed subjects, putting us right on track to meet our recruitment targets. Preliminary examination of the data being collected on the GCRC protocol shows that all variables are within the expected range and showing expected changes - e.g., increased cardiovascular and neuroendocrine arousal with anger recall challenge. The tryptophan depletion protocol is functioning as expected, with plasma tryptophan levels falling to very low levels on the tryptophan depletion day. With 17% of the total sample now run, we have not begun data analyses regarding the major hypotheses. Inspection of the data currently available in conjunction with the aforementioned checks for appropriate range and responsivity has revealed a rather intriguing serendipitous finding. Among the first 11 subjects run through the tryptophan depletion arm, those with high CSF 5HIAA (indicating high brain serotonin turnover) have higher resting plasma norepinephrine (NE) than subjects with lower CSF 5HIAA prior to consuming the amino acid drink with tryptophan included on the first, placebo day. At 30 min. after consuming the drink, all Ss show a spike in NE that is larger in high 5HIAA Ss, despite their higher baseline level. On the second test day, at 30 min following consumption of the drink not containing tryptophan, the high 5HIAA Ss show a larger NE spike than on the placebo day, while the low 5HIAA Ss show a smaller peak. While the ultimate meaning of this observation remains to be determined, it is quite interesting that tryptophan depletion has opposite effects on plasma NE response to the unpleasant drink in high vs low 5HIAA Ss - suggesting that the CSF 5HIAA measure will produce important findings when we move toward our planned, more systematic analyses of the data. Even though not proposed in our original application, we have been collecting pilot data on a recently discovered serotonin transporter promoter polymorphism. The promoter region for the serotonin transporter has two alleles in humans, one long (l) and one short (s). Persons with the l/l genotype have been shown to make more transporter and to score lower on measures of neurotocism than persons with l/s or s/s. A recent study by Higley et al. found that the l/l genotype was associated with higher CSF 5HIAA levels in rhesus monkeys who were separated from their mothers from birth to six months of age. In mother-reared monkeys, however, transporter promoter genotype was unrelated to CSF 5HIAA. We will be able to evaluate this same relationship in the subjects being studied under our GCRC protocol - i.e., to test whether the l/l genotype is more strongly associated with higher CSF 5HIAA in lower than higher SES Ss. Significance: Results should enhance our understanding of the environmental and neurobiological bases of the clustering of psychosocial/biobehavioral risk factors and lead to improved approaches to prevention and treatment of cardiovascular disease.