COCAINE--EFFECT ON FETAL BRAIN METABOLISM AND FUNCTION

描述：（申请人摘要） 孕妇使用可卡因仍然是一个重大的公共卫生问题。 最近 报告显示，10-15%的来自市中心人口的新生儿 在子宫内接触可卡因 虽然我们现在知道了很多关于 单剂量可卡因对母亲和母亲的生理影响 胎儿，几乎没有什么是已知的这些影响时，可卡因已 管理，因为它通常是在怀孕，这是重复超过一个 延长了一段时间。 我们建议进行研究， 反复接触可卡因对大脑发育的影响。 具体来说，我们将研究胎儿的循环和代谢， 大脑长期暴露于可卡因，胎儿行为状态的改变 这种暴露引起的，以及已知的神经受体的改变， 在可卡因的神经药理学中很重要 本提案的目标 是三重的。 首先，以怀孕的绵羊为模型，我们将 确定长期服用可卡因对一些重要的 母体和胎儿基础生理参数。 科帕卡巴纳将是 在怀孕的后半段每天给母羊服用，之后我们 将研究产妇的血压、心率和子宫血流， 以及胎儿血压、心率、行为状态， 下丘脑-垂体-肾上腺轴激素与脑和心肌 血流和氧化代谢在一个休息，非应激条件。 此外，我们将使用相同的动物模型，研究局部脑 胎儿葡萄糖利用率作为功能性中枢神经系统的标志 系统变更。 其次，我们将确定胎儿是否发育 由对可卡因的生理反应确定的对可卡因的耐受性 作为一种新的，首次暴露与可卡因暴露相比， 胎儿生命的持续时间。 此外，我们将确定可卡因是否 代谢和清除以及血浆儿茶酚胺浓度 可卡因在这些动物中发生了改变， 他们第一次接触这种药物 第三，我们将确定 重复可卡因暴露对大鼠海马神经元密度和分布的影响 已知胎儿中的受体直接或间接受 可卡因;特别是多巴胺D1和D2受体，多巴胺再摄取位点， 以及NMDA和非NMDA谷氨酸受体。

DESCRIPTION: (Applicant's Abstract) Cocaine use by pregnant women remains a major public health issue. Recent reports reveal that 10-15% of neonates from inner city populations have been exposed to cocaine in-utero. Although we now know much about the physiological effects of a single dose of cocaine in both the mother and the fetus, virtually nothing is known about these effects when cocaine has been administered as it usually is in pregnancy, that is repetitively over a prolonged period of time. We are proposing studies designed to examine the effects of repeated exposures to cocaine on the developing brain. Specifically, we will study the circulation and metabolism of the fetal brain chronically exposed to cocaine, alterations in fetal behavioral state induced by this exposure, and alterations in neural receptors known to be important in cocaine's neuropharmacology. The objectives of this proposal are threefold. First, using the pregnant sheep as a model, we will determine the effects of chronic cocaine administration on some important maternal and fetal basal physiological parameters. Cocaine will be administered daily to the ewe over the 2nd half of pregnancy after which we will study maternal blood pressure, heart rate and uterine blood flow as well as fetal blood pressure, heart rate, behavioral state, hypothalamic-pituitary-adrenal axis hormones and cerebral and myocardial blood flow and oxidative metabolism during a resting, non-stress condition. In addition, using the same animal model, we will study local cerebral glucose utilization in the fetus as a marker for functional central nervous system alterations. Second, we will determine if the fetus develops tolerance to cocaine as determined by the physiological responses to cocaine administered as a novel, first time exposure versus cocaine exposure for a significant duration of fetal life. Further, we will determine if cocaine metabolism and clearance and plasma catecholamine concentrations following cocaine are altered in these animals compared to animals receiving their first exposure to the drug. Third, we will determine the effects of repetitive cocaine exposure on the density and distribution of neural receptors in the fetus known to be either directly or indirectly affected by cocaine; specifically dopamine D1 and D2 receptors, dopamine reuptake sites, and NMDA and non-NMDA glutamate receptors.