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（CHD）的病因、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)评估相互关联的社会心理风险因素与发病机制的行为和生物（包括细胞/分子水平）介质之间的关联；2)识别增加发病机制的社会心理/生物行为特征的环境前因；3)在人类和动物模型中评估脑血清素功能降低作为某些个体和低社会经济地位群体聚集的社会心理和生物行为介质的可能作用。方法：我们正在招募一个社区样本400名受试者，按社会经济地位、种族和性别分层，他们将在我们的GCRC住院2.5天期间进行研究。在此期间，他们将接受腰椎穿刺，提供脑脊液（CSF），以测定CSF 5-羟基吲哚乙酸（5HIAA），这是衡量中枢神经系统血清素转换的可靠指标。他们还将使用色氨酸消耗法进行血清素消耗，并使用iv色氨酸增强血清素。我们将评估和比较SES和CSF 5HIAA与心理社会和生物行为风险因素的关系，以及血清素消耗和增强对情绪、心血管和神经功能的影响，以及对这些功能对精神挑战的反应。结果：我们现在已经通过GCRC方案运行了35个受试者，按照目前的受试者累积率，我们预计到7月30日当前资助期结束时，我们将有超过60个完成的受试者，使我们正确地实现我们的招聘目标。对GCRC方案收集的数据的初步检查表明，所有变量都在预期范围内，并显示出预期的变化——例如，愤怒回忆挑战增加了心血管和神经内分泌唤醒。色氨酸耗竭方案如预期的那样发挥作用，血浆色氨酸水平在色氨酸耗竭日降至非常低的水平。现在运行了总样本的17%，我们还没有开始对主要假设进行数据分析。结合上述对适当范围和响应性的检查，对现有数据的检查揭示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，在第一天服用含色氨酸的氨基酸饮料之前，CSF 5HIAA高（表明脑5 -羟色胺转化率高）的受试者的静息血浆去甲肾上腺素（NE）高于CSF 5HIAA低的受试者。在喝完饮料30分钟后，尽管他们的基线水平较高，但所有高5HIAA的人的NE峰值都更大。在第二个测试日，在饮用不含色氨酸的饮料后30分钟，高5HIAA s的NE峰值比安慰剂日更大，而低5HIAA s的峰值更小。虽然这一观察结果的最终意义仍有待确定，但有趣的是，色氨酸消耗对高5HIAA和低5HIAA Ss的血浆NE反应有相反的影响，这表明当我们朝着我们计划的、更系统的数据分析方向发展时，CSF 5HIAA测量将产生重要的发现。尽管在我们最初的应用程序中没有提出，但我们一直在收集最近发现的血清素转运蛋白启动子多态性的试点数据。人类血清素转运体的启动子区域有两个等位基因，一个长(l)，一个短(s)。l/l基因型的人比l/s或s/s基因型的人产生更多的转运蛋白，在神经功能障碍的测量中得分较低。Higley等人最近的一项研究发现，从出生到6个月与母亲分离的恒河猴中，l/l基因型与较高的CSF 5HIAA水平相关。然而，在母猴中，转运子启动子基因型与CSF 5HIAA无关。我们将能够在GCRC方案下研究的受试者中评估同样的关系-即，测试l/l基因型是否与低SES比高SES更强烈地与高CSF 5HIAA相关。意义：结果将增强我们对社会心理/生物行为风险因素聚类的环境和神经生物学基础的理解，并导致改进心血管疾病的预防和治疗方法。

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.