HMG COA REDUCTASE INHIBITION AND BEHAVIOR

HMG COA 还原酶抑制和行为

• 批准号: 2655206
• 负责人: m. babette Fontenot
• 金额: $ 5.23万
• 依托单位: WAKE FOREST UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 1994
• 资助国家: 美国
• 起止时间: 1994-02-01 至 1998-09-15
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2655206
• 关键词: HMG coA reductases; Macaca fascicularis; aggression; antihypercholesterolemic agent; autoradiography; behavior test; behavioral /social science research tag; cardiovascular pharmacology; cholesterol; cholestyramine; diet therapy; dietary lipid; ethology; fenfluramine; gender difference; high performance liquid chromatography; hydroxyindoleacetate; neuropharmacologic agent; neuropharmacology; neurotransmitter metabolism; nutrition related tag; oxidoreductase inhibitor; psychobiology; reducing diet; serotonin; social behavior

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.

建议通过饮食或药物方法降低胆固醇， 所有美国人，尽管没有对照研究评估， 这种干预的生物行为或其他健康影响。等 作为一般医疗谨慎的问题，评价是必要的，因为 建议对最初健康的个体进行干预。一个更 许多研究的结果提供了具体的理由， 血浆胆固醇浓度降低或临床降低至显著水平 与暴力有关的死亡率（事故、自杀、他杀）增加， 萧条在拟议的研究中，行为和神经生物学 将应用不可能用于健康人类志愿者的程序 对食蟹猴（Macaca fascicularis）进行生物行为学评价 降低胆固醇的后遗症。在这个实验中，我们将研究 成年雄性和雌性猴各30只， 经历由饮食和饮食引起的胆固醇显著降低， 药理学手段。这是一个受试者内设计，所有动物 依次暴露于3个7个月的治疗：1）低脂肪饮食， 胆固醇，根据目前的饮食建议（lofat）建模; 2）a 高脂肪和高胆固醇的饮食，模仿典型的美国人 消费（hifat）;和3）hifat饮食加消胆胺， 许多流行病学试验中使用的降胆固醇药物。猴子 将被安置在社会群体中，每五只动物一组， 实验将收集社会交往的行为样本 在每个治疗阶段定期进行。其他测量将包括 血浆胆固醇浓度，脑脊液5- 羟吲哚乙酸浓度和外周肾上腺素能 刺激.申请人将调查两个主要假设：1） 通过低脂饮食或消胆胺降低血浆胆固醇 会引起攻击性增加和社交能力下降; 2）任何 这种由降低胆固醇引起的行为变化将是 伴随着中枢多巴胺能活性降低。体外 将应用放射自显影技术来检验以下假设： 增加的攻击性是由于中枢神经系统的改变， 摄取亲和力和/或分布。该提案的第一阶段将包括 的：1）研究生水平的课程工作在分子神经生物学，细胞和 生物化学神经科学、神经行为药理学和临床 神经科学，必要的追求研究项目，2）旋转 通过共同赞助商的实验室学习技术，其中包括 高效液相色谱法和体外放射自显影; 3） 在申办者实验室进行初步工作，以收集基线行为 和临床数据。在第二阶段，将准备一份正式的研究提案 并提交给了教师评审