COCAINE AND BRAIN DEVELOPMENT

本提案的总体目标是建立动物模型 该系统将有助于调查可卡因的影响 暴露在发育中的大脑中 具体来说，一种技术， 人工饲养新生RAS将用于表征 可卡因暴露引起的神经形态学变化 大脑生长突增期，大脑生长最快的时期。那段时间， 大致相当于人类妊娠晚期， 发育中的大脑特别容易受到 其他侮辱。第一个目标是确定基本的 可卡因在新生大鼠体内的发育药代动力学特性 使用人工饲养程序。第一个假设是 测试表明，在大脑快速生长期间， 产生发育迟缓的大脑生长（microencephaly）无论是在一个临时或 永久的基础。 第二个假设是， 大脑生长突增导致神经元数量减少， 大脑不同区域的神经元表现出不同的脆弱性 可卡因。 最先进的体视学计数技术将 用于提供整个人口的准确定量估计， 海马结构中的锥体细胞和颗粒细胞，以及浦肯野氏细胞 和小脑中的颗粒细胞。 第三个要检验的假设 在妊娠晚期接触可卡因 在血管破裂和反应性星形胶质细胞增生中， 新皮层胶质细胞酸性蛋白（GFAP）免疫细胞化学 将被用来识别整个大脑中受影响的区域。 的 阐明结构性脑损伤的类型和位点， 在大脑快速生长期间暴露于可卡因将有助于 确定大脑发育的阶段， 以及在确定是否有模式和时间 可卡因暴露的程度会影响损害的类型或程度。 这些 研究还将有助于全面了解 哺乳动物大脑的结构性损伤 在其最迅速的时期接触可卡因后， 发展

The overall objective of this proposal is to establish an animal model system which will be useful for investigating the effects of cocaine exposure on the developing brain. Specifically, a technique for artificially rearing neonatal ras will be used to characterize neuromorphological changes resulting from cocaine exposure during the brain growth spurt, the period of most rapid brain growth. That period, which is roughly equivalent to that of the human third trimester, is a time when the developing brain is especially vulnerable to the effects of other insults. The first objective will be to determine basic developmental pharmacokinetic properties of cocaine in the neonatal rats using the artificial-rearing procedure. The first hypothesis to be tested is that cocaine exposure during the brain growth spurt can produce stunted brain growth (microencephaly) either on a temporary or permanent basis. The second hypothesis is that cocaine exposure during the brain growth spurt causes reductions in neuronal populations, and that neurons in various brain regions exhibit differential vulnerability to cocaine. State-of-the-art stereological counting techniques will be used to provide accurate quantitative estimates of entire populations of pyramidal and granule cells in the hippocampal formation, and Purkinje and granule cells in the cerebellum. The third hypothesis to be tested is that cocaine exposure during the third trimester equivalent results in vascular disruption and reactive astrogliosis especially in the neocortex. Glial fibrillary acidic protein (GFAP) immunocytochemistry will be used to identify affected regions throughout the brain. The elucidation of the types and loci of structural brain damage resulting from cocaine exposure during the brain growth spurt will be helpful in identifying stages of development when the brain is especially vulnerable to cocaine and in determining whether the pattern and timing of the cocaine exposure influences the type or extent of damage. These studies will also contribute to establishing a comprehensive picture of the spectrum of structural damage to the mammalian brain that can occur following cocaine exposure during the period of its most rapid development.