HMG COA REDUCTASE INHIBITION AND BEHAVIOR

建议通过饮食或药物方法降低胆固醇 所有美国人，尽管缺乏评估 这种干预的生物行为或其他健康影响。是这样的 评估是值得的，作为一般医学审慎的问题，因为 建议对最初健康的个人进行干预。A更多 大量研究的结果提供了具体的理论基础。 低或临床降低的血浆胆固醇浓度到显著 与暴力有关的死亡率(事故、自杀、凶杀)和 抑郁症。在拟议的研究中，行为和神经生物学 不可能在健康的人类志愿者身上使用的程序将被应用 对食蟹猴(Macaca Fascular Aris)的生物学行为进行评价 降胆固醇的后遗症。在这个实验中，我们将研究 雄性和雌性成年猕猴各30只的行为和神经生物学功能 由饮食和饮食引起的显著的胆固醇降低 药理学手段。这是一个受试者内部的设计，所有的动物 依次接受3次为期7个月的治疗：1)低脂肪饮食和 胆固醇，仿照当前的饮食建议(LOFAT)；2)a 高脂肪和高胆固醇的饮食，模仿典型的美国人 摄取(HIFAT)；和3)HIFT饮食加上氯乙酸胺，A 在许多流行病学试验中使用的降胆固醇药物。猴子们 将被安置在以五只动物为一组的社交团体中 做实验。将收集社交互动的行为样本 在每一个疗程中都是常规的。其他衡量标准将包括 血浆胆固醇浓度，脑脊液5- 羟吲哚乙酸浓度和外周5-羟色胺能 刺激。申请者将调查两个主要假设：1) 通过低脂饮食或氯乙四胺降低血浆胆固醇 会导致攻击性增加和社交能力下降；以及2)任何 这种由降低胆固醇引起的行为变化将是 伴随着中枢5-羟色胺能活动的降低。离体 放射自显影技术将被用来检验这一假设 中枢5-羟色胺能改变导致侵袭性增加 摄取、亲和和/或分布。该提案的第一阶段将包括 1)研究生水平的课程，分子神经生物学，细胞和 生化神经科学、神经行为药理学和临床 神经科学，进行研究项目所必需的，2)轮换 通过共同赞助商的实验室学习技术，包括 高效液相色谱和体外放射自显影 在赞助商的实验室中收集基线行为的初步工作 和临床数据。在第二阶段，将编写一份正式的研究提案 并提交给教员进行审查。

Cholesterol reduction by dietary or pharmacologic means is recommended for all Americans despite the absence of controlled studies evaluating the biobehavioral or other health effects of this intervention. Such evaluation is warranted as a matter of general medical prudence, since the intervention is recommended for initially healthy individuals. A more specific rationale is provided by the results of numerous studies linking low or clinically reduced plasma cholesterol concentrations to significant increases in violence-related mortality (accident, suicide, homicide) and depression. In the proposed research, behavioral and neurobiologic procedures impossible to use on healthy human volunteers will be applied to cynomolgus macaques (Macaca fascicularis) to evaluate the biobehavioral sequelae of cholesterol lowering. In this experiment, we will study the behavior and neurobiologic function of 30 male and 30 female adult monkeys undergoing significant cholesterol reduction induced by both dietary and pharmacologic means. This is a within-subjects design, with all animals exposed in turn to 3 seven-month treatments: 1) a diet low in fat and cholesterol, modeled after current dietary recommendations (lofat); 2) a diet high in fat and cholesterol, modeled after typical American consumption (hifat); and 3) the hifat diet plus cholestyramine, a cholesterol-lowering drug used in many epidemiologic trials. The monkeys will be housed in social groups of five animals each for the entire experiment. Behavioral samples of social interactions will be collected routinely in each treatment period. Additional measurements will include plasma cholesterol concentration, cerebrospinal fluid 5- hydroxyindoleacetic acid concentration, and peripheral serotonergic stimulation. The applicant will investigate two major hypotheses are: 1) lowering plasma cholesterol by either the lofat diet or cholestyramine will provoke increased aggression and decreased sociability; and 2) any such behavioral changes induced by cholesterol lowering will be accompanied by reduced central serotonergic activity. In vitro autoradiographic techniques will be applied to test the hypothesis that increased aggressivity results from alterations of central serotonergic uptake affinity and/or distribution. Phase I of the proposal will consist of:1)graduate level course work in molecular neurobiology, cellular and biochemical neuroscience, neurobehavioral pharmacology, and clinical neuroscience, necessary to pursue the research project, 2) rotation through the co-sponsor's laboratory to learn techniques, which include high performance liquid chromatography and in vitro autoradiography and 3) initial work in the sponsor's laboratory to collect baseline behavioral and clinical data. In Phase II a formal research proposal will be prepared and submitted for faculty review.