DRUG INTERACTIONS WITH DEVELOPING MYELIN SYSTEMS

本研究旨在分析发展中国家的脆弱性， 大脑和恢复潜力，暴露于主要的，非法的 滥用药物。 五年的资金要求允许 研究异常的潜在机制，以及 相关的副现象。 作为一个流行病的比例问题， 美国，药物滥用的健康风险进一步加剧，特别是 在生育率最高的年份（青少年后期和 20）。 胎儿通过母亲的血液接触，婴儿接触 包括吮吸乳汁，其可在哺乳期内输送活性物质。 血液中的浓度，甚至更高。 大脑的发育是由一系列 阶段，从子宫内开始，然后是出生后的大脑生长 喷射。 每一个新的阶段都可以被认为是一个关键时期，尽管 大脑的不同部分可能在不同的时间表达不同的阶段， 次 人类的髓鞘形成跨越了从第三个三个月到 童年. 老鼠的大脑发育得与人类大脑相似， 提出了一个有据可查的模型系统，用于评价毒性。 的 髓磷脂发育的细胞和生物化学方面已经显示， 是发展中特别脆弱的关键阶段。 这种粗放 记录为类似的药物评价提供了坚实的基础 毒性，包括有问题的副作用，如营养， 停药、暴露持续时间和间隔时间等。 髓鞘的合成和积累将与 髓鞘形成细胞数量的超微结构研究 有髓轴突的数量、无髓轴突的数量、髓鞘/轴突 关系，和神经元，等等。从这些协调的研究，它将 可以表征各种初级和次级 异常的表现。 苯二氮卓类药物、可卡因、大麻， 安非他明，苯环，LSD和海洛因/美沙酮是针对 为期5年的初步研究。 剂量将跨越一个有意义的范围，至少 两个订单，将被选择来模拟从高到 在人类中很低。 预测两者共同的正态方差的程度 大脑发育中的渐进事件（细胞增殖， 髓鞘形成等），和退化事件（细胞死亡，突触 消除等），提出的表征实验设计 药物暴露的影响将避免经常发现的相互矛盾的结果， 用少量老鼠进行的有限的调查。

This research is designed to analyze vulnerabilities of the developing brain, and recovery potential, following exposure to the major, illicit drugs of abuse. Five years of funding is requested to permit investigations of the underlying mechanisms of abnormality, as well as of associated epiphenomena. As a problem of epidemic proportions in the U.S.A., the health risks of drug abuse are further compounded by especially high rates of abuse during the years of greatest fertility (late teens and 20's). Fetal exposure is via the mother's blood, and infant exposure includes the suckling of milk, which may convey active substances at the concentration in blood, or even higher. The brain develops as a series of stages, starting in utero and followed by the postnatal brain growth spurt. Each new stage may be thought of as a critical period, although different parts of the brain may express different stages at different times. Myelination in humans spans a time from the 3rd trimester through childhood. The rat brain, which develops similarly to the human brain, presents a well documented, model system for evaluating toxicity. The cellular and biochemical aspects of myelin development have been shown to be an especially vulnerable, critical stage in development. This extensive record provides a solid foundation for similar evaluations of drug toxicity, including problematic epiphenomena, such as nutrition, withdrawal, duration and intervals of exposure, etc. Multifaceted studies of myelin synthesis and accumulation will be correlated with ultrastructural studies of the numbers of myelin-forming cells, the numbers of myelinated axons, numbers of non-myelinated axons, myelin/axon relationships, and neurons, etc. From these coordinated studies, it will be possible to characterize a wide range of primary and secondary manifestations of abnormality. Benzodiazepines, cocaine, marijuana, amphetamines, phenycyclidines, LSD, and heroine/methadone are targeted for an initial 5-year study. Dosages will span a meaningful range of at least two orders, which will be selected to mimick exposure ranging from high to low in humans. Anticipating the extent of normal variance common to both the progressive events in brain development (cell multiplication, myelination, etc.), and the regressive events (cell death, synapse elimination, etc.), the experimental design proposed for characterizing influences of drug exposure will avoid the often conflicting results found in limited surveys with small numbers of rats.