DRUG INTERACTIONS WITH DEVELOPING MYELIN SYSTEMS

这项研究旨在分析开发中的漏洞 大脑，和恢复潜力，在接触到主要的，非法的 滥用药物。需要五年的资金才能允许 调查异常的根本机制，以及 相关的附随现象。作为一个流行病比例的问题， 在美国，吸毒的健康风险进一步加剧，尤其是 生育率最高年份的高虐待率(青少年后期和 20‘S)。胎儿接触是通过母亲的血液，而婴儿接触 包括哺乳，这可能会在乳汁中传递活性物质 血液中的浓度，甚至更高。大脑发育成一系列的 阶段，从子宫开始，然后是出生后的大脑发育 冲刺。每个新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阶段表达不同的信息 泰晤士报。人类的髓鞘形成时间跨度从妊娠晚期一直持续到 童年。老鼠的大脑，它的发育与人脑相似， 提出了一个有充分证据的评估毒性的模型系统。这个 髓鞘发育的细胞和生化方面已被证明 在发展中处于特别脆弱的关键阶段。如此广泛 记录为类似的药物评价提供了坚实的基础 毒性，包括有问题的附带现象，如营养， 戒断、持续时间和暴露间隔等多方面的研究 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、非有髓轴突数量、髓鞘/轴突 关系和神经元等。从这些协调研究中，它将 有可能描述出一系列主要和次要的 异常的表现。苯二氮卓类，可卡因，大麻， 苯丙胺、苯环利定、LSD和海洛因/美沙酮是针对 最初为期5年的研究。剂量将跨越一个有意义的范围，至少 两个顺序，将被选择来模拟暴露，范围从高到 在人类中很低。预测两者共有的正态方差的程度 大脑发育中的进步事件(细胞增殖， 髓鞘形成等)和退行性事件(细胞死亡、突触 消除等)，建议用于表征的实验设计 药物暴露的影响将避免经常发现的相互矛盾的结果 在对少量老鼠进行的有限调查中。

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.