SNRP at Hunter College

亨特学院 SNRP

• 批准号: 7349998
• 负责人: Jesus A Angulo
• 金额: $ 12.16万
• 依托单位: HUNTER COLLEGE
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-09-01 至 2008-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7349998
• 关键词: cell death; data collection; detoxification; dopamine; glutamates; human; injury; interneurons; learning; methamphetamine; motivation; neurons; neuropeptide receptor; receptor; role; somatostatin; substance P; toxin; university

Methamphetamine (METH) use is increasing in the United States. Striatal deficits in humans induced by METH persist after detoxification and protracted abstinence and have been associated with impairment of motor tasks and learning. Our lab discovered that pharmacological blockade of the striatal neurokinin-1 receptor (NK-1R) confers protection from METH to both dopamine (DA) terminals and striatal neurons. This interesting and novel finding needs further investigation because it provides a therapeutic target for the treatment of METH abuse. Our working hypothesis is that the excessive DA released in response to METH, interacts with substance P-containing striatal neurons. This in turn causes excessive release of substance P (SP), which then acts through NK-1Rs on cholinergic and somatostatin/NOS interneurons. In the latter neurons, nNOS is up-regulated and excessive NO produced. We suggest that the excessive NO is what is causing the loss of DA-terminals and neuronal cell death in the striatum. This hypothesis will be tested by the following specific aims: Aim 1: The purpose of this aim is to test the hypothesis that SP induces striatal injury in the presence of METH. To this end, the selective SP agonist GR73632 will be utilized to exacerbate METH-induced striatal neural damage. Aim 2: The purpose of this aim is to test the hypothesis that the striatal NK-1 Rs signal neural damage in the presence of METH. To this end, the striatal NK-1 R-expressing cells will be destroyed with.the selective toxin SSP-saporin. Aim 3: The purpose of this aim is to test the hypothesis that SP modulates striatal NO production. To this end, neurochemical and histological methods will be utilized to establish a connection between the striatal NK-1 Rs and the glutamate/NO neurotoxic cascade. The overall, long-term goal of these studies is to define the role of the NK-1Rs in the striatal injury induced by METH. The information gathered may prove valuable for the treatment of METH abuse and may also describe a role for this receptor in the striatum.

在美国，甲基苯丙胺 (METH) 的使用量正在增加。人类纹状体缺陷由以下因素引起 戒毒和长期戒酒后，冰毒仍然存在，并与功能障碍有关。 运动任务和学习。我们的实验室发现纹状体神经激肽-1 的药理学阻断 受体 (NK-1R) 为多巴胺 (DA) 末端和纹状体神经元提供免受 METH 的保护。这 有趣且新颖的发现需要进一步研究，因为它为以下疾病提供了治疗靶点： 冰毒滥用的治疗。我们的工作假设是，过量的 DA 因冰毒而释放， 与含有 P 物质的纹状体神经元相互作用。这反过来又导致P物质的过度释放 (SP)，然后通过 NK-1R 作用于胆碱能和生长抑素/NOS 中间神经元。在后者中 神经元中，nNOS 上调并产生过量的 NO。我们建议过量的NO是什么 导致纹状体中 DA 末端的丢失和神经元细胞死亡。这个假设将被检验 以下具体目标： 目标 1：该目标的目的是检验 SP 在存在以下物质的情况下诱发纹状体损伤的假设： 方法。为此，选择性 SP 激动剂 GR73632 将用于加剧 METH 诱导的纹状体 神经损伤。 目标 2：该目标的目的是检验纹状体 NK-1 Rs 信号神经损伤的假设 冰毒的存在。为此，纹状体 NK-1 R 表达细胞将被选择性破坏。 毒素SSP-皂草素。 目标 3：该目标的目的是检验 SP 调节纹状体 NO 产生的假设。对此 最后，将利用神经化学和组织学方法来建立纹状体之间的联系 NK-1 Rs 和谷氨酸/NO 神经毒性级联反应。 这些研究的总体长期目标是确定 NK-1R 在纹状体损伤中的作用 由冰毒引起。收集到的信息可能对治疗冰毒滥用很有价值，并且可能 还描述了该受体在纹状体中的作用。