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。近期 报告显示，来自市中心人口的新生儿中有10%-15%是 在宫内暴露于可卡因。虽然我们现在知道了很多关于 单剂量可卡因对母体和母体的生理影响 胎儿，几乎对这些影响一无所知，当可卡因 就像通常在怀孕时一样，在一个月内重复给药 延长一段时间。我们正在提议进行研究，旨在研究 反复接触可卡因对发育中大脑的影响。 具体地说，我们将研究胎儿的循环和代谢 长期接触可卡因的大脑，胎儿行为状态的改变 由这种暴露引起的，以及已知的神经受体的变化 在可卡因的神经药理学中很重要。这项提案的目标是 是三重的。首先，以怀孕的绵羊为模型，我们将 确定长期使用可卡因对某些重要疾病的影响 孕妇和胎儿的基本生理参数。可卡因将会是 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、心率和子宫血流量 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 静息、非应激状态下的血流和氧化代谢。 此外，使用相同的动物模型，我们将研究局部大脑 胎儿葡萄糖利用作为功能性中枢神经标志物的研究 系统改造。第二，我们将确定胎儿是否发育 可卡因的生理反应决定对可卡因的耐受性 作为一种新的首次接触与可卡因接触相比， 显著延长胎儿的生命周期。此外，我们将确定可卡因是否 代谢和清除与血浆儿茶酚胺浓度 与服用可卡因的动物相比，这些动物体内的可卡因发生了变化 他们第一次接触这种药物。第三，我们将确定 可卡因重复暴露对神经密度和分布的影响 已知胎儿中的受体直接或间接受 可卡因；具体地说，多巴胺D1和D2受体，多巴胺再摄取部位， 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.