MONOAMINE DEVELOPMENT FOLLOWING IN UTERO DRUG EXPOSURE

描述：（申请人摘要） 产前暴露于精神兴奋药物对胎儿发育影响的研究 发育中的单胺能神经元受到许多实验的限制， 变量包括剂量、给药方案、胎龄、 暴露和出生后年龄，在后代进行检查。 鉴于这些 复杂性，关于这个问题的研究很少，尽管 普遍认识到暴露于有毒物质的严重公共卫生问题， 胎儿对具有神经毒性潜力的药物的敏感性。 已知产前药物暴露 导致发展中国家的神经，认知和行为缺陷， 这可能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，我们建议利用三维重组组织 文化系统，我们已经表明，提供了适当的屏幕， 子宫内药物暴露对完整脑的影响， “精确”的临界剂量和暴露时间，用于设计体内 实验 该培养系统提供了一种体外培养的方法， 特定神经元投射的重建和发育， 类似于完整大脑的回路。 形成的重新聚集体 从分离的胚胎细胞，包含完整的，功能和 相互作用的单胺能神经元， 药理学和毒理学试剂，其方式与 在体内观察到的。 能够维持这样的重建 神经元投射的时间延长，长达一年， 允许人们在整个过程中监测药物诱导的作用， 神经元从胎儿到成人阶段的发育历史。 具体来说，我们打算通过以下方法监测多巴胺能和多巴胺能功能： 测量神经递质释放以及单胺组织水平， 在子宫内将这些神经元暴露于通常的 使用了精神兴奋剂冰毒 这种体外实验的结果 研究将用于设计实验，以验证和扩展这些 体内发现。 甲基苯丙胺诱导的改变的直接比较 单胺能功能在体外和体内已经证明， 这种做法的有效性。 此外，重组问题文化 系统将用于确定子宫内是否暴露于 甲基苯丙胺导致单胺能神经元的脆弱性增加 与普通治疗剂的神经毒性作用有关， 哌甲酯，用于治疗儿童注意力缺陷 精神障碍，芬氟拉明，一种食欲抑制剂，或甲基苯丙胺， 常用的精神兴奋剂 本提案的目标是 提供一种评估神经毒理学风险的实用方法， 孕妇在怀孕早期和怀孕后期使用的精神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.