PSYCHOMOTOR STIMULANTS AND DOPAMINE RECEPTOR DEVELOPMENT

精神运动兴奋剂和多巴胺受体的发育

• 批准号: 2122536
• 负责人: BETHANY S NEAL-BELIVEAU
• 金额: $ 7.63万
• 依托单位: INDIANA UNIV-PURDUE UNIV AT INDIANAPOLIS
• 依托单位国家: 美国
• 财政年份: 1994
• 资助国家: 美国
• 起止时间: 1994-04-01 至 1995-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2122536
• 关键词: biological models; brain mapping; cocaine; developmental neurobiology; dopamine; dopamine antagonists; dopamine receptor; embryo /fetus toxicology; in situ hybridization; laboratory rat; methamphetamine; newborn animals; serotonin; serotonin inhibitor; synaptogenesis

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.

尿液中患有非法物质的婴儿的发病率 在过去的十年中，大大增加了，主要是由于增加 在使用心理运动兴奋剂（PMS）中，例如可卡因（COC）和 甲基苯丙胺（地图）。 随着这些孩子的出生，动物 研究确定围产期暴露的后果 药物变得更加重要。 研究计划的长期目标 是检查PMS的神经化学和行为后果 在大鼠开发期间的不同时间暴露，以建模 人类怀孕。 对于此提案，药物暴露将仅限于 大鼠早期的早期孕育于三个月的人 接触。 在突触中作用的药物的第三学期给药 特别有害，因为这个时期的特征是 突触发生和树突状树博化。 围产期PMS暴露是 已知对神经行为的发育有不利影响。 这些 药物通过大脑中的多巴胺（DA）和5-羟色胺（5-HT）水平 导致和/或阻止摄取突触前神经元。 因为DA和5-HT充当增长调节剂，所以 发育可能会改变正常的突触发生。 地图处理也是 据报道要通过慢性治疗破坏DA神经元。 DA耗竭 在发育过程中，会在动物中产生行为障碍， 疾病的类型和范围取决于病变的时间。 这 该提议的目的是确定是否：（1）PMS治疗期间 关键时期对DA系统具有永久影响； （2） 如果是这样，是否取决于药物治疗的时间； （3）它们是否涉及内在组织的改变 纹状体，称为补丁/矩阵组织。 老鼠幼崽会 在第一周的不同时间段内处理了WIT COC或MPA 生活。 PMS治疗的行为和神经化学后果 将被检查。 定量受体放射自显影将用于 量化和定位在成年大脑中的DA受体。 标记 突触前末端将用于确定药物治疗是否具有 对DA神经元的永久作用。 原位杂交组织化学 将用于测量编码酪氨酸羟化酶的mRNA水平（ DA）的合成酶，作为神经元损伤的敏感指标。 斑块和基质的免疫细胞化学和组织化学标记 车厢将用于确定早期PMS治疗是否干扰 纹状体内在组织的发展。 行为功能将通过查看对选择性的响应来检查 DA受体激动剂和拮抗剂，以及认知测试和测试 对于敏化的存在。 初步检查 血清素能功能将被执行，因为已知PM会影响PM 5-HT水平。 这项研究的结果将提供起点 对于有兴趣检查的长期研究计划 PMS暴露在各个过程中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，并使我们深入了解 开发暴露于PMS的婴儿的干预策略。