PSYCHOMOTOR STIMULANTS AND DOPAMINE RECEPTOR DEVELOPMENT

婴儿出生时尿液中含有非法物质的发生率 在过去10年里，这一数字大幅增加，主要是由于 在使用精神兴奋剂（PMS），如可卡因（COC）和 甲基苯丙胺（MAP）。 随着越来越多的孩子出生，动物 研究，以确定围产期暴露于这些 药物变得越来越重要。 研究计划的长期目标 是研究经前综合症的神经化学和行为后果 在大鼠发育过程中的不同时间暴露，以模拟 人类怀孕 对于本提案，药物暴露将仅限于 大鼠生后早期妊娠晚期模型 exposure. 作用于突触的药物的晚期给药 尤其具有破坏性，因为这一时期的特点是， 突触发生和树突分支。 围产期PMS暴露是 对神经行为发育有不良影响 这些 药物通过改变大脑中的多巴胺（DA）和5-羟色胺（5-HT）水平， 导致从突触前神经元释放和/或阻断摄取进入突触前神经元。 由于DA和5-HT作为生长调节剂， 发育可能改变正常的突触发生。 MAP治疗也是 据报道，长期治疗会破坏DA神经元。 DA耗竭 在发育过程中产生的动物行为障碍， 疾病的类型和范围取决于病变的时间。 的 本提案的目的是确定：（1）PMS治疗期间 关键发展期对DA系统具有永久性影响; 如果是，其影响是否取决于药物治疗的时间; 以及（3）它们是否涉及改变的内在组织， 纹状体，被称为补丁/矩阵组织。 幼鼠将会 在第一周的不同时间段给予COC或MPA 生命 经前综合症治疗的行为和神经化学后果 将被审查。 定量受体放射自显影将用于 定量和定位成年大脑中的DA受体。 标志物 突触前末梢将用于确定药物治疗是否具有 对DA神经元的永久性影响。 原位杂交组织化学 将被用于测量编码酪氨酸羟化酶的mRNA水平（ DA合成酶），作为神经元损伤的敏感指标。 补片和基质的免疫细胞化学和组织化学标记 隔室将用于确定早期PMS治疗是否会破坏 纹状体内在组织的发展。 行为功能将通过观察对选择性 DA受体激动剂和拮抗剂，以及认知测试和测试 是否存在致敏性。 初步审查 因为经前综合症已知会影响 5-HT水平。 这项研究的结果将提供一个起点， 一个长期的研究项目， PMS暴露的神经化学和行为影响， 发展阶段 这项工作应该有助于我们理解 围产期药物暴露的后果，并让我们深入了解 为暴露于PMS的婴儿制定干预策略。

The incidence of infants born with illicit substances in their urine has increased greatly over the past 10 years, primarily due to an increase in the use of psychomotor stimulants (PMS) such as cocaine (COC) and methamphetamine (MAP). As more of these children are born, animal studies to determine the consequences of perinatal exposure to these drugs become more important. The long term goal of the research program is to examine the neurochemical and behavioral consequences of PMS exposure at various times during rat development to model the stages of human pregnancy. For this proposal, drug exposure will be limited to the early postnatal period of the rat to model third trimester human exposure. Third trimester administration of drugs acting at the synapse is particularly damaging because this period is characterized by synaptogenesis and dendritic arborization. Perinatal PMS exposure is known to have adverse effects on neurobehavioral development. These drugs alter dopamine (DA) and serotonin (5-HT) levels in the brain by causing release from and/or blocking uptake into the presynaptic neuron. Because DA and 5-HT act as growth regulators, altered levels during development may alter normal synaptogenesis. MAP treatment is also reported to destroy DA neurons with chronic treatment. DA depletion during development produces behavioral disorders in animals, with the type and range of disorders depending upon timing of the lesion. The aims of this proposal are to determine if: (1) PMS treatment during critical periods of development has permanent effects on DA system; (2) If so, are the effects dependent upon the timing of the drug treatment; and (3) Do they involve alterations in the intrinsic organization f he striatum, known as the patch/matrix organization. Rat pups will be treated wit COC or MPA at different time periods during the first week of life. The behavioral and neurochemical consequences of PMS treatment will be examined. Quantitative receptor autoradiography will be used to quantify and localize DA receptors in the adult brain. Markers of the presynaptic terminal will be used to determine if drug treatment has permanent effects on DA neurons. In situ hybridization histochemistry will be used to measure mRNA levels coding for tyrosine hydroxylase (the synthetic enzyme for DA), as a sensitive indicator of neuronal damage. Immunocytochemical and histochemical marker of the patch and matrix compartments will be used to determine if early PMS treatment disrupts the development of the intrinsic organization of the striatum. Behavioral function will be examined by looking at responses to selective DA receptor agonist and antagonist, as well as cognitive tests and tests for the presence of sensitization. A preliminary examination of serotonergic function will be carried out because PMS are known to affect 5-HT levels. The results of this study will provide the starting point for a long-term research program interested in examining the neurochemical and behavioral effects of PMS exposure during the various stages of development. This work should aid in our understanding of the consequences of perinatal drug exposure, and give us insights into the development of intervention strategies for infants exposed to PMS.