PSYCHOMOTOR STIMULANTS AND DOPAMINE RECEPTOR DEVELOPMENT

婴儿出生时尿液中含有非法物质的发生率为 在过去10年中大幅增长，主要是由于 在使用精神运动兴奋剂(PMS)，如可卡因(COC)和 冰毒(MAP)。随着越来越多的孩子出生，动物 确定围产期暴露于这些物质的后果的研究 毒品变得更加重要。这项研究计划的长期目标 是检查经前综合症的神经化学和行为后果 在大鼠发育过程中不同时间的暴露以模拟不同阶段的 人类怀孕。对于这项提议，接触毒品将被限制在 大鼠出生后早期建立晚期妊娠模型的研究 曝光。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 突触发生和树突分枝。围产期经前综合症的暴露是 已知对神经行为发育有不利影响。这些 药物通过以下方式改变大脑中的多巴胺和5-羟色胺水平 导致突触前神经元释放和/或阻止摄取。 由于DA和5-羟色胺作为生长调节剂，在 发育可能会改变正常的突触发生。MAP治疗也是 据报道，慢性治疗可以破坏DA神经元。DA耗竭 在发育过程中会产生动物的行为障碍， 疾病的类型和范围取决于病变的时间。这个 这项提案的目的是确定：(1)经前综合症的治疗是否在 发展的关键时期对发展援助制度产生永久性影响；(2) 如果是，效果是否取决于药物治疗的时机； 以及(3)它们是否涉及内部组织的变化 纹状体，称为斑块/基质组织。幼鼠将会是 在第一周的不同时间段使用COC或MPA治疗 生活的一部分。经前综合征治疗的行为和神经化学后果 将会被检查。定量受体放射自显影将用于 对成人大脑中的多巴胺受体进行量化和定位。标记物： 突触前终末将被用来确定药物治疗是否 对DA神经元的永久性影响。原位杂交组织化学 将用于测量编码酪氨酸羟化酶( 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 将使用隔间来确定早期经前综合症治疗是否中断 纹状体内部组织的发育。 行为功能将通过观察对选择性的反应来检查 DA受体激动剂和拮抗剂，以及认知测试和测试 因为有敏化的存在。对…的初步考察 5-羟色胺能功能将被执行，因为已知经前综合症会影响 5-羟色胺水平。这项研究的结果将提供起点 对于一个长期的研究计划，有兴趣研究 经前综合征暴露对大鼠神经化学和行为的影响 发展的各个阶段。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 针对暴露于经前综合症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.