MONOAMINE DEVELOPMENT FOLLOWING IN UTERO DRUG EXPOSURE

描述：(申请人摘要) 产前接触精神运动刺激剂对儿童精神障碍影响的研究 单胺能神经元的发育受到许多实验的限制 变量包括剂量、给药方案、孕周、持续时间 对后代进行检查的暴露和出生后年龄。考虑到这些 复杂性，关于这个问题的研究数量很少，尽管有 公众普遍认识到暴露于 将胎儿转移到具有神经毒性的药物。产前药物暴露是已知的 导致发育中的神经、认知和行为缺陷 在整个过程中会影响这些人的心理健康 他们的生活史。为了简化这样的实验要求 研究中，我们建议利用三维重组组织 文化系统，我们已经展示了该系统为 作为一种手段，宫内药物暴露对完整大脑的影响 体内设计的“指针式”临界剂量和暴露时间 实验。该培养体系为体外培养提供了一种方法。 特异神经元投射的重建和发展 与完好无损的大脑中的电路类似。重新聚集，形成了 从分离的胚胎细胞中分离出来，包含完整的、有功能的和 相互作用的单胺能神经元发育和反应 药理和毒物的作用方式与 在活体内观察到的。有可能保持这样的重建 长时间的神经元投射，长达一年， 允许一个人在整个过程中监测药物诱导的影响 神经元从胎儿到成人期的发育史。 具体地说，我们打算通过以下方式监测多巴胺和5-羟色胺能功能 测量神经递质释放以及单胺组织水平 这些神经元在宫内暴露于常见的 使用精神运动兴奋剂，冰毒。这种体外实验的结果 研究将被用于设计实验来验证和扩展这些 活体内的发现。甲基苯丙胺引起的改变的直接比较 在体外和体内的单胺能功能已经证明 这一方法的有效性。此外，重组发行文化 系统将被用来确定在子宫内是否暴露于 甲基苯丙胺导致单胺能神经元易损性增加 对常见治疗药物的神经毒性作用，如 哌醋甲酯用于儿童注意力缺陷的治疗 紊乱，芬氟拉明，一种食欲抑制药，或甲基苯丙胺，一种 常用的精神运动兴奋剂。这项建议的目标是 提供一种实用的方法来评估神经毒理学风险 孕期女性使用的精神运动兴奋剂对胎儿的影响 怀孕中期。

DESCRIPTION: (Applicant's Abstract) Studies on the effects of prenatal exposure to psychomotor stimulants on developing monoaminergic neurons are limited by a number of experimental variables including dosage, dosage regimen, gestational age, duration of exposure and postnatal age at which the progeny are examined. Given these complexities, studies on this issue have been few in number despite the general awareness of the severe public health problem of exposure of the fetus to agents with neurotoxic potential. Prenatal drug exposure is known to result in neurologic, cognitive and behavioral deficits in the developing human which can affect the mental health of such individuals throughout their life history. In order to simplify the experimental demands of such studies, we propose to utilize the three-dimensional reaggregate tissue culture system, which we have shown provides an appropriate screen for effects of in utero drug exposure in the intact brain, as a means of `pin-pointing' critical doses and exposure times for design of in vivo experiments. This culture system provides a method for the in vitro reconstruction and development of specific neuronal projections with circuitry similar to that in the intact brain. The reaggregates, formed from disassociated embryonic cells, contain intact, functioning and interacting monoaminergic neurons which develop and respond to pharmacological and toxicological agents in a manner remarkably similar to that observed in vivo. It has been possible to maintain such reconstructed neuronal projections for extended periods of time, up to one year, permitting one to monitor drug-induced effects during the entire developmental history of neurons from the fetal to the adult stage. Specifically, we intend to monitor dopaminergic and serotonergic function by measuring neurotransmitter release as well as monoamine tissue levels over time in culture following in utero exposure of such neurons to a commonly used psychomotor stimulant, methamphetamine. The results of such in vitro studies will be used to design experiments to verify and extend these findings in vivo. Direct comparison of methamphetamine-induced alterations in monoaminergic function in vitro and in vivo have already demonstrated the validity of this approach. In addition, the reaggregate issue culture system will be used to determine whether in utero exposure to methamphetamine results in increased vulnerability of monoaminergic neurons to the neurotoxic effects of common therapeutic agents such as methylphenidate, used in the treatment of children with Attention Deficit Disorder, fenfluramine, an appetite suppressant, or methamphetamine, a commonly used psychomotor stimulant. The objectives of this proposal are to provide a practical approach to the assessment of neurotoxicological risk to the fetus of psychomotor stimulants used by pregnant females in early and mid-gestation.